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This study answers the question of origin and evolution of a granulitic microstructure typically developed in felsic granulites of the European Variscan belt. It shows that the precursor of the Variscan felsic granulites was a high-pressure alkali feldspar-rich coarse-grained layered orthogneiss. Its S1 subhorizontal layering is defined by the alignment of alkali feldspar porphyroclasts alternating with monomineralic bands of quartz and bands rich in plagioclase and garnet. The alkali feldspar porphyroclasts contain inclusions of quartz, garnet, kyanite, biotite and rutile, reflecting peak P-T conditions of 1.6-1.8 GPa and 850 °C during S1 formation. Superimposed steep folds and steep cleavage, S2, are associated with recrystallization of alkali feldspar, plagioclase and quartz, and garnet chemistry modifications that correspond to 0.9-1.0 GPa and 800 °C. During exhumation, involving 0.8 GPa decompression and cooling, the probably perthitic alkali feldspar underwent an unusual process of heterogeneous decomposition along irregular reaction fronts forming a fine-grained matrix composed of plagioclase and K-feldspar grains. Regular grain distributions in the matrix, nucleation-dominated crystal size distribution and preservation of lattice orientation of the parental perthite crystals are all explained by a discontinuous precipitation process. This heterogeneous decomposition of alkali feldspar solid solution is controlled by chemically and strain induced grain-boundary migration. During exhumation and decompression, the fine-grained matrix underwent viscous deformation, forming the typical microstructure of the Variscan granulites. Random phase distributions, minor coarsening and feldspar textures are interpreted as a result of strain softening due to diffusion creep-accommodated grain-boundary sliding. Subordinate large quartz ribbons were rheologically stronger than the feldspar-dominated matrix due to the activity of different deformational mechanisms. Finally, in mid-crustal levels, the subvertical structure was overprinted by a perpendicular steep fabric associated with the growth of sillimanite, heterogeneous hydration and local partial melting, development of aggregate phase distributions and significant coarsening. This evolution is accompanied with the development of a strong lattice preferred orientation of quartz, K-feldspar and plagioclase, reflecting a switch to dislocation creep mechanism and a general hardening of the granulites under amphibolite facies conditions. [ABSTRACT FROM AUTHOR]

The structure of the Moldanubian domain is marked by felsic granulites of Ordovician protolith age forming the cores of domes that are separated from mid-crustal Neoproterozoic and Palaeozoic metasedimentary rocks that occur in synclines by a late Ordovician to Silurian metabasic unit. Reflection and refraction seismic sections combined with gravity inversion modelling suggest the presence of a low density layer at the bottom of the crust (interpreted as felsic granulite) overlain by a denser layer (interpreted as amphibolite) with layers of intermediate density at the top (interpreted as metasedimentary rocks). It is proposed that the granulite domes surrounded by middle crustal rocks reflect transposed horizontal layering originally similar to that preserved in the deep crust and imaged by the geophysical surveys. This geological and geophysical structure is considered to be a result of Viséan gravity redistribution initiated by radioactive heating of felsic crust tectonically emplaced at the bottom of a Palaeozoic orogenic root. The radioactive layer with heat production of 4 μW m corresponds geochemically and isotopically to Ordovician felsic metaigneous rocks of the Saxothuringian domain that have been emplaced at Moho depth under thickened crust during late Devonian-early Carboniferous continental subduction. Part of the continental crust continued to be subducted and produced fluids/low-volume melts which directly contaminated and enriched the local lithospheric mantle by lithophile elements, most notably Cs, Rb, Li, Pb, U, Th and K. Thermal incubation of 10-15 Myr was sufficient to heat and convert the underplated felsic layer into granulites via dehydration melting and melt segregation. The process of melt loss was responsible for the removal of radioactive elements and for switching off the heat at the beginning of the exhumation process. At the same time, the metasomatized underlying mantle was heated producing characteristic ultrapotassic magmas. Gravitational instability was then induced by the density contrast between the light granulites and the overlaying denser mafic lower crustal layer and a viscosity drop related to thermal weakening and partial melting of the latter. [ABSTRACT FROM AUTHOR]

Reflection seismic section, field structural analysis and gravimetric modelling of orogenic lower crust in the core of a Carboniferous orogenic root reveal details of the polyphase process of exhumation. Subvertical amphibolite facies fabrics strike parallel to former plate margins that collided in the NW. The fabrics are developed in both mid-crustal and lower crustal high-pressure granulite units as a result of intensive NW-SE intraroot horizontal shortening driven probably by the west-directed collision. In granulites, the steep fabrics originated as a result of extrusion of orogenic lower crust in a ∼20 km wide vertical ascent channel from lower crustal depths at 350-340 Ma. The large granulite bodies preserve older granulite facies fabrics documenting a two-stage evolution during the exhumation process. Surface exposures of granulites coincide with the absence of subhorizontal seismic reflectors at depth, suggesting preservation of the ∼20 km wide subvertical tabular structure reaching Moho depths. Horizontal seismic reflectors surrounding the vertical channel structure corroborate a dominant flat migmatitic fabric developed in all tectonic units. This structural pattern is interpreted in terms of subhorizontal spreading of partially molten orogenic lower crust in mid-crustal levels (765 °C and 0.76 GPa) at 342-337 Ma. Large massifs of extruded and progressively dismembered felsic granulites disturbed mid-crustal fabrics in the surrounding horizontally flowing partially molten crust. The horizontal mid-crustal flow resulted in collapse of the supra-crustal Teplá-Barrandian Unit (interpreted as the orogenic lid) along a large-scale crustal detachment above the extruded lower crustal dome. The presence of felsic granulites at the bottom of the orogenic root is considered to be a key factor controlling the exhumation of orogenic lower crust in large hot orogens. [ABSTRACT FROM AUTHOR]

Gneisses and migmatites of the Gföhl unit (Moldanubian Zone, Bohemian Massif) range from banded mylonitic orthogneiss with recrystallized monomineralic bands, through stromatic (metatexite) and schlieren (inhomogeneous diatexite) migmatite, to isotropic nebulite (homogeneous diatexite). This sequence was classically attributed to increasing degree of anatexis. Under the microscope, the evolution is characterized by progressive destruction of the monomineralic banding that characterizes the original mylonitic orthogneiss. Throughout, the mineral assemblage is biotite–K-feldspar–plagioclase–quartz ± garnet ± sillimanite, but the mineral compositions exhibit systematic changes with progressive disintegration of the layering. From banded orthogneiss to nebulite, the garnet composition changes systematically, Alm75→94Prp17→0.8Grs2.5→1.2Sps2→11 and XFe = 0.45→0.99 and for biotite, XFe = 0.80→1. This is consistent with a decrease in equilibration temperature and pressure of 790 °C and 8.5–6 kbar, to 690 °C and 5–4 kbar respectively. There is also a systematic change of whole-rock composition, marked by an increase in SiO2 (71→77 wt%) and XFe (0.62→0.85) and by a decrease in Al2O3 (16→13 wt%) and CaO (1.50→0.43 wt%). Assuming that the rocks started with the same composition, these systematic changes indicate open-system behaviour. The predicted consequences of various open-system processes are assessed using thermodynamic modelling. The observed variations are interpreted as being a consequence of melt flow through, and interaction with the rocks, and, to change the rock composition sufficiently, a large volume of melt must have been involved. [ABSTRACT FROM AUTHOR]

In the scope of a prospective multi-centre study after neoadjuvant combined chemotherapy (carboplatin, ifosfamide, etoposide, vindesine) and radiotherapy (45 Gy) 40 resection specimens of locally advanced non-small-cell lung cancer were analysed in order to establish reproducible pathological/anatomical results of tumour regression. Resection specimens of 28 squamous cell carcinomas and 12 adenocarcinomas were investigated using serial sections of the primary lesion. The mean age of the patients was 57 years. The results were compared to spontaneous regressive changes in a control group of 50 untreated non-small-cell lung cancers. Marked scarry fibrosis in the region of the former primary tumour, concentric foci of fresh tumour necroses and surrounding foam cell clusters with transition into vascular granulation tissue could be established as characteristic features of therapy-induced tumour regression, whereas untreated carcinomas revealed necroses with adjoining vital tumour tissue. Using a threestep regression system, 3 tumours could be classified as grade I (no or only slight tumour regression), 10 tumours as grade IIA (marked but incomplete tumour regression, more than 10% vital tumour tissue), 20 tumours as grade IIB (less than 10% vital tumour tissue) and 7 tumours as grade III (complete tumour regression without vital tumour tissue). After a median follow-up period of 32.3 months in patients with grade IIB or III tumour regression (“responders”) the median survival time of 27.9 months was found to be significantly longer than in patients with grade I or IIA tumour regression (“non-responders”) with a median survival period of 13.7 months (log-rank test, P=0.020). The resection specimens analysed, which were obtained 7 weeks (on average) after the end of radiochemotherapy, did not show specific changes due to preoperative therapy, but quite characteristic histological alterations in the former tumour area were registered, which had been induced by combined neoadjuvant radiation and chemotherapy. The grade of therapy-induced tumour regression could be shown to be a significant prognostic factor in non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]

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A letter to the editor is presented which discusses the risk of small bowel cancer in patients with hereditary non-polyposis colorectal cancer (HNPCC).

Abstract: Recent petrological, structural and geochronological studies of the eastern margin of the Bohemian Massif (Czech Republic) suggest a conceptual geodynamical model to explain exhumation of lower crustal (20kbar, 800°C) felsic rocks. The model involves indentation of a weak orogenic lower crust by an adjacent rigid mantle lithosphere, resulting in crustal-scale buckling of the weak orogenic lower/middle crust interface followed by extrusion of a ductile nappe over the rigid promontory. The hypothesis has been investigated using both analogue and numerical models. Analogue experiments using a three layer sand-silicone setup were carried out in Rennes laboratory (France). Results show that the most important features of the conceptual model can be reproduced: extrusion of lowermost silicone over the indenter and flow of horizontal viscous channel underneath a rigid lid above the actively progressing promontory. Furthermore, experimental results show that a plateau develops above the channelling lower crust. Two sets of sandbox-scale numerical simulations were performed. The first set of experiments is designed to study the influence of viscosity stratification within the crust on the extrusion process. A second set of experiments were performed in order to quantify the influence of the viscosity and the geometry of the indentor. Non-dimensional scaling laws were derived to predict the maximum extrusion rates associated with the indentation mechanism. Such laws enable the computation vertical extrusion rates that are in good agreement with natural exhumation rates inferred from petrological data. Finally, we discuss the potential positive feedback of Rayleigh–Taylor instability on vertical extrusion for the case of Eastern Bohemian Massif. [Copyright &y& Elsevier]

Abstract: The Gföhl Unit is the largest migmatite terrain of the Variscan orogenic root domain in Europe. Its genesis has been until now attributed to variable degrees of in situ partial melting. In the Rokytná Complex (Gföhl Unit, Czech Republic) there is a well-preserved sequence documenting the entire migmatitization process on both outcrop and regional scales. The sequence starts with (i) banded orthogneiss with distinctly separated monomineralic layers, continuing through (ii) migmatitic mylonitic gneiss, (iii) schlieren migmatite characterised by disappearance of monomineralic layering and finally to (iv) felsic nebulitic migmatite with no relics of the original banding. While each type of migmatite shows a distinct whole-rock geochemical and Sr–Nd isotopic fingerprint, the whole sequence evolves along regular, more or less smooth trends for most of the elements. Possible mechanisms which could account for such a variation are that the individual migmatite types (i) are genetically unrelated, (ii) originated by equilibrium melting of a single protolith, (iii) formed by disequilibrium melting (with or without a small-scale melt movement) or (iv) were generated by melt infiltration from external source. The first scenario is not in agreement with the field observations and chemistry of the orthogneisses/migmatites. Neither of the remaining hypotheses can be ruled out convincingly solely on whole-rock geochemical grounds. However in light of previously obtained structural, petrologic and microstructural data, this sequence can be interpreted as a result of a process in which the banded orthogneiss was pervasively, along grain boundaries, penetrated by felsic melt derived from an external source. In terms of this melt infiltration model the individual migmatites can be explained by different degrees of equilibration between the bulk rock and the passing melt. The melt infiltration can be modelled as an open-system process, characterised by changes of the total mass/volume and accompanied by gains/losses in many of the major- and trace elements. The modelling of the mass balance resulted in identification of a component added by a heterogeneous nucleation of feldspars, quartz and apatite from the passing melt. This is in line with the observed presence of new albitic plagioclase, K-feldspar and quartz coatings as well as resorption of relict feldspars. At the most advanced stages (schlieren and nebulitic migmatites) the whole-rock trace-element geochemical variations document an increasing role for fractional crystallization of the K-feldspar and minor plagioclase, with accessory amounts of monazite, zircon and apatite. The penetrating melt was probably (leuco-) granitic, poor in mafic components, Rb rich, with low Sr, Ba, LREE, Zr, U and Th contents. It probably originated by partial melting of micaceous quartzo-feldspathic rocks. If true and the studied migmatites indeed originated by a progressive melt infiltration into a single protolith resembling the banded orthogneiss, this until now underappreciated process would have profound implications regarding rheology and chemical development of anatectic regions in collisional orogens. [Copyright &y& Elsevier]

Highly deformed banded phengite–biotite metagranite from the Snieznik dome in the Bohemian Massif has been modified locally to have stromatic, schlieren or nebulitic textures typical of migmatites. This occurred mostly along subvertical deformation zones at eclogite-facies conditions, at a scale of several centimetres to several metres, mostly parallel to the foliation. The transition from banded to migmatite types of orthogneiss is marked by an increase in the amount of phases interstitial along grain boundaries in the dynamically recrystallized monomineralic feldspar and quartz aggregates, and by increasing consumption of recrystallized K-feldspar grains by fine-grained plagioclase and quartz, as well as myrmekite (intergrowth of Pl−Qz). The new minerals are in textural equilibrium with phengite. The myrmekite, quartz and feldspars can be coarse-grained (grain size ≤0·5 cm). These features are considered to be the result of grain-scale melt infiltration that caused dissolution–reprecipitation along grain boundaries in the presence of phengite. The infiltration was pervasive at the grain scale, but localized at hand-specimen to outcrop scales. All the rock types have the same mineral assemblage of Grt−Ph−Bt−Ttn−Kfs−Pl−Qz±Rt±Ilm; they have similar garnet, phengite and biotite compositions, and based on mineral equilibria modelling we infer equilibration at a pressure of 1·5–1·7 GPa and a temperature of 690–740°C. Because the rocks are inferred to be H2O-undersaturated and above the temperature conditions of the wet solidus, infiltration must have involved a hydrous melt, as opposed to an H2O fluid. Stability of melt-bearing mineral assemblages and mineral compositions are almost independent of the melt proportion in the system, thus explaining the identical assemblage and mineral compositions observed in all the migmatite types. This precludes the estimation of the amount of melt infiltrated. Migmatite textures, however, suggest that variable degrees of melt–rock interaction occurred, being low in the banded migmatite types and higher in the nebulitic and schlieren types. Retrograde equilibration was largely restricted to retrograde zoning in phengite, garnet and plagioclase, and crystallization of biotite around phengite and garnet, presumably in a continuous reaction consuming melt. This may have occurred down to ∼0·7–1·0 GPa. According to Sr–Nd isotope data, the infiltrating melt is probably derived from similar rocks, structurally beneath the observed ones. The infiltration may have facilitated exhumation of a 2 km wide structural domain from ∼1·7 to ∼0·7 GPa, within which are the subvertical deformation zones along which the infiltration occurred. [ABSTRACT FROM AUTHOR]

Viscosity contrasts displayed in flow structures of a mountain namakier (Kuh-e-Namak - Dashti), between ‘weak’ second phase bearing rock salt and ‘strong’ pure rock salt types are studied for deformation mechanisms using detailed quantitative microstructural study. While the solid inclusions rich (“dirty”) rock salts contain disaggregated siltstone and dolomite interlayers, “clean” salts reveal microscopic hematite and remnants of abundant fluid inclusions in non-recrystallized cores of porphyroclasts. Although the flow in both, the recrystallized “dirty” and “clean” salt types is accommodated by combined mechanisms of pressure-solution creep (PS), grain boundary sliding (GBS), transgranular microcracking and dislocation creep accommodated grain boundary migration (GBM), their viscosity contrasts observed in the field outcrops are explained by: 1) enhanced ductility of “dirty” salts due to increased diffusion rates along the solid inclusion-halite contacts than along halite–halite contacts, and 2) slow rates of intergranular diffusion due to dissolved iron and inhibited dislocation creep due to hematite inclusions for “clean” salt types Rheological contrasts inferred by microstructural analysis between both salt rock classes apply in general for the “dirty” salt forming Lower Hormuz and the “clean” salt forming the Upper Hormuz of the Hormuz Formation and imply strain rate gradients or decoupling along horizons of mobilized salt types of different composition and microstructure. [ABSTRACT FROM AUTHOR]

Monazite laser ablation-split-stream inductively coupled plasma-mass spectrometry (LASS) was used to date monazite in situ in Barrovian-type micaschists of the Moravian zone in the Thaya window, Bohemian Massif. Petrography and garnet zoning combined with pseudosection modelling show that rocks from staurolite-chlorite, staurolite, kyanite and kyanite-sillimanite zones record burial in the S1 fabric under a moderate geothermal gradient from 4-4·5 kbar and ~530-540°C to 5 kbar and 570°C, 6-7 kbar and 600-640°C, 7·5-8 kbar and 630-650°C, and 8 kbar and 650°C, respectively. In the kyanite and kyanite-sillimanite zones, garnet rim chemistry and local syntectonic replacement of garnet by sillimanite-biotite aggregates point to re-equilibration at 5·5-6 kbar and 630-650°C in the S2 fabric. Heterogeneously developed retrograde shear zones (S3) are marked by widespread chloritization, but minor chlorite is present in the studied samples. Monazite abundance and size increase with metamorphic grade from 5 µm in the staurolite-chlorite zone to >100 µm in the kyanite and kyanite-sillimanite zones. Irrespective of the monazite-forming reaction, this is interpreted as the onset of limited prograde monazite growth at staurolite grade, and continued prograde monazite growth after the kyanite-in reaction, compatible with conditions of about 5·5 kbar and 570°C and 7·5 kbar and 630°C from pseudosection modelling. Monazite is zoned, showing embayments and sharp boundaries between zones, with low Y in the staurolite zone, high-Y cores and low-Y rims in the kyanite zone, and high-Y cores, a low-Y mantle and a high-Y rim in the sillimanite zone. The 207Pb-corrected 238U/206Pb ages from three samples range from 344 ± 7 to 330 ± 7 Ma, irrespective of metamorphic grade. The dates from monazite inclusions are interpreted as the ages of the staurolite- and kyanite-in reactions along the prograde path at 340 and 337 ± 7 Ma, respectively. The monazite in the matrix (and some inclusions) is interpreted as dating the prograde crystallization at (340-337) ± 7 Ma within the S1 fabric, and then being affected by recrystallization at or down to 332 ± 7 Ma in the S2 and S3 fabrics. The two groups of data, for 340-337 and 332 Ma, are significantly different when only their in-run uncertainties (±1-3 Myr) are compared and indicate a 9 ± 3 Myr period of monazite (re)crystallization. A systematic increase in heavy rare earth element (HREE) content with decreasing monazite age from 344 to 335 Ma is correlated with growth on the prograde P-T path; the drop in HREE of monazite at 335-328 Ma is assigned to recrystallization. The presence of chlorite even in the least retrogressed samples witnesses limited external fluid availability on the retrograde P-T path. Migration of this fluid was probably responsible for heterogeneous fluid-assisted recrystallization and resetting of original prograde monazite, even where included in garnet, staurolite or kyanite. It is suggested that the rocks passed the chlorite-in reaction on the retrograde path at 332 ± 7 Ma. The timing of burial in the Thaya window, a deformed part of the underthrust Brunia microcontinent, was coeval with exhumation of granulites and migmatites of the Moldanubian orogenic root at c. 340 Ma. [ABSTRACT FROM AUTHOR]

The present work examines the lithological, structural, geochemical and geochronological records from the Klippen Belt located in the southern Vosges Mountains (NE France). The Klippen Belt is represented by discontinuous exposures of serpentinized harzburgite, ophicalcite, gabbro, gneiss and polymictic conglomerate overlain by deep marine pelitic sediments. Structural data and Bouguer anomalies reveal that the Klippen Belt coincides with a significant discontinuity now occupied by a granitic ridge. Gabbro geochemistry indicates a MOR-type affinity similar to recent slow-spreading ridges, but positive Ba, Sr, Th or U anomalies do not exclude the influence of fluids expelled from a subduction zone. A Sm-Nd isochron age of 372 ± 18 Ma is thought to reflect gabbro emplacement from a highly depleted mantle source (ε = +11.3), and U-Pb zircon ages from a gneiss sample indicate that the basement found in the Klippen has a Neoproterozoic origin. Combined data indicate the formation of a deep basin during Late Devonian rifting. The Klippen lithologies could testify for the presence of an ocean-continent transition environment subsequently inverted during the Early Carboniferous. Basin inversion during the Middle Visean was probably controlled by rift-related structures, and resulted in folding of the sedimentary successions as well as exhumation along thrust zones of deep parts of the basin represented by the Klippen Belt. Based on correlations with the neighbouring Variscan massifs, it is proposed that the southern Vosges sequences represent a back-arc basin related to the North-directed subduction of the southern Palaeotethys Ocean. This geodynamic reconstruction is tentatively correlated with similar ophiolitic remnants in the northern part of the French Massif Central (Brévenne) and with the evolution of the southern Black Forest. The Late Devonian ophiolites are interpreted as relicts of small back-arc marginal basins developed during general closure of the Palaeozoic subduction systems. [ABSTRACT FROM AUTHOR]

The monoclonal antibody pertuzumab represents the first HER2 dimerization inhibitor with unknown activity in colon cancer treatment. We examined the antitumor activity of pertuzumab as a single agent or in combination with erlotinib or irinotecan in human colon cancer cells in vitro and in vivo. Colon cancer cell lines were tested for HER1/HER2 expression by western blot analysis. The effect of pertuzumab on cell cycle distribution was analyzed by FACS. Nude mice bearing xenograft tumors were treated with pertuzumab alone, or in combination either with irinotecan or with erlotinib. Tumor volume was measured repeatedly. Tumor histology was analyzed for necrosis. Six of nine cell lines showed high expression of HER1/HER2. Pertuzumab inhibited cell cycle progression in various cell lines. Pertuzumab showed minor antitumor activity in xenograft tumors, but significantly inhibited tumor growth when combined with erlotinib ( P < 0.001). Combination of pertuzumab with irinotecan had no additional effect on growth of additional tumors. Pertuzumab treated DLD-1 xenograft tumors did not show enhanced necrosis, which, however, was found in HCT116 derived xenografts. Pertuzumab has some antitumor activity on human colon cancer cells in vitro and in vivo, in particular when combined with erlotinib. In vivo, pertuzumab combination treatment was not superior to irinotecan monotherapy. These data warrant further investigation of simultaneous HER1/EGFR TKI inhibition and HER1/HER2 dimerization inhibition for colorectal cancer therapy. [ABSTRACT FROM AUTHOR]

To investigate the relationship between Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), we determined gene expression profiles of discrete pathological stages of esophageal neoplasia using a sequence-verified human cDNA microarray. Fifty one RNAs, comprising 24 normal esophagi (NE), 18 BEs, and nine EACs were hybridized to cDNA microarrays. Five statistical analyses were used for the data analysis. Genes showing significantly different expression levels among the three sample groups were identified. Genes were grouped into functional categories based on the Gene Ontology Consortium. Surprisingly, the expression pattern of BE was significantly more similar to EAC than to NE, notwithstanding the known histopathologic differences between BE and EAC. The pattern of NE was clearly distinct from that of EAC. Thirty-six genes were the most differentially modulated, according to these microarray data, in BE-associated neoplastic progression. Twelve genes were significantly differentially expressed in cancer-associated BE's plus EAC (as a single combined tissue group) vs noncancer-associated BE's. These genes represent potential biomarkers to diagnose EAC at its early stages. Our results demonstrate that molecular events at the transcriptional level in BE are remarkably similar to BE's-associated adenocarcinoma of the esophagus. This finding alarmingly implies that BE is biologically closer to cancer than to normal esophagus, and that the cancer risk of BE is perhaps higher than we had imagined. These findings suggest that changes modulated at the molecular biologic level supervene earlier than histologic changes, and that BE is an early intermediate stage in the process of EAC.Oncogene (2006) 25, 3346–3356. doi:10.1038/sj.onc.1209357; published online 30 January 2006 [ABSTRACT FROM AUTHOR]

A continuous, but attenuated section through orogenic lower and middle crust overthrust by a second lower-crustal complex was distinguished at the eastern margin of the Bohemian Massif. This indicates the existence of two lower-crustal “autochthonous” extrusions into middle crust that is not compatible with the model of “allochthonous” lower crustal klippen remaining after flat thrusting of the Gföhl nappe over large distances. The base of the lower crust is represented by a granulite body exhumed from c. 15 kbar and 800 °C. A hangingwall complex of layered amphibolites gradually passes into amphibolite bearing paragneisses (the Monotonous unit) and micaschists intercalated with marbles at the top (the Varied unit). The metamorphic grade and anatexis decreases upwards and the micaschists preserve a prograde path to c. 8 kbar and 700 °C. This sequence is overthrust by a second lower crustal strongly migmatitized complex, referred to as the Raabs complex, which is marked by an eclogite-bearing belt at the base. The garnet zoning of eclogite indicates burial from 10 kbar to min. 15 kbar. In all units, relics of a steep metamorphic fabric were identified, reworked by folding and a moderately west-dipping foliation. The conditions of 7–10 kbar and approximately 750 °C for the flat foliation were obtained in all units indicating that exhumation of the lower crust into a middle crustal level occurred earlier, probably during the development of steep fabrics. The intense flat fabric is interpreted as a result of thrusting of the whole assembly over the middle crustal Brunian indentor. [ABSTRACT FROM AUTHOR]

Background: Effective governance arrangements are central to the successful functioning of health systems. While the significance of governance as a concept is acknowledged within health systems research, its interplay with health system reform initiatives remains underexplored in the literature. This study focuses on the development of new regional health structures in Ireland in the period 2018-2023, one part of a broader health system reform programme aimed at greater universalism, in order to scrutinise how aspects of governance impact on the reform process, from policy design through to implementation., Methods: This qualitative, multi-method study draws on document analysis of official documents relevant to the reform process, as well as twelve semi-structured interviews with key informants from across the health sector. Interviews were analysed according to thematic analysis methodology. Conceiving governance as comprising five domains (Transparency, Accountability, Participation, Integrity, Capacity) the research uses the TAPIC framework for health governance as a conceptual starting point and as initial, deductive analytic categories for data analysis., Results: The analysis reveals important lessons for policymakers across the five TAPIC domains of governance. These include deficiencies in accountability arrangements, poor transparency within the system and vis-à-vis external stakeholders and the public, and periods during which a lack of clarity in terms of roles and responsibilities for various process and key decisions related to the reform were identified. Inadequate resourcing of implementation capacity, competing policy visions and changing decision-making arrangements, among others, were found to have originated in and continuously reproduced a lack of trust between key institutional actors. The findings highlight how these challenges can be addressed through strengthening governance arrangements and processes. Importantly, the research reveals the interwoven nature of the five TAPIC dimensions of governance and the need to engage with the complexity and relationality of health system reform processes., Conclusions: Large scale health system reform is a complex process and its governance presents distinct challenges and opportunities for stakeholders. To understand and be able to address these, and to move beyond formulaic prescriptions, critical analysis of the historical context surrounding the policy reform and the institutional relationships at its core are needed., (© 2024. The Author(s).)

Background: The von Willebrand factor-directed nanobody caplacizumab has greatly changed the treatment of immune thrombotic thrombocytopenic purpura (iTTP) in recent years. Data from randomized controlled trials established efficacy and safety., Objectives: This study aims to address open questions regarding patient selection, tailoring of therapy duration, obstacles in prescribing caplacizumab in iTTP, effect on adjunct treatment, and outcomes in the real-world setting., Methods: We report retrospective, observational cohorts of 113 iTTP episodes treated with caplacizumab and 119 historical control episodes treated without caplacizumab. We aggregated data from the caplacizumab phase II/III trials and real-world data from France, the United Kingdom, Germany, and Austria (846 episodes, 396 treated with caplacizumab, and 450 historical controls)., Results: Caplacizumab was efficacious in iTTP, independent of the timing of therapy initiation, but curtailed the time of active iTTP only when used in the first-line therapy within 72 hours after diagnosis and until at least partial ADAMTS13-activity remission. Aggregated data from multiple study populations showed that caplacizumab use resulted in significant absolute risk reduction of 2.87% for iTTP-related mortality (number needed to treat 35) and a relative risk reduction of 59%., Conclusion: Caplacizumab should be used in first line and until ADAMTS13-remission, lowers iTTP-related mortality and refractoriness, and decreases the number of daily plasma exchange and hospital stay. This trial is registered at www., Clinicaltrials: gov as #NCT04985318., Competing Interests: Declaration of competing interests L.A.V. received speaker honoraria and consultant fees from Sanofi-Genzyme and AstraZeneca. J.K. reports speaker honoraria and participation on advisory boards from Alexion, Sanofi, and Chiesi. W.M. reports grants from Takeda/Shire and CSL Behring and received speaker honoraria and consultant fees from Takeda/Shire and CSL Behring. P.T.B. received speaker honoraria and consultant fees from Sanofi-Genzyme, AstraZeneca, Alexion, Bayer, Travere, Pfizer, Novartis, Roche, and participated in advisory boards for Alexion, Sanofi-Genzyme, Novartis, Travere, and Bayer. He declares research funding from the German Research Foundation BR-2955/8. R.W. received speaker honoraria and consultant fees from Sanofi-Genzyme. He additionally declares research funding from the German Federal Ministry of Education and Research and the German Federal Ministry of Health. U.S. reports study fees and/or consultancy/advisory board fees from Chemocentryx/Vifor, Ablynx/Genzyme-Sanofi, Alexion, Travere, Alynlam Pharmaceuticals, and Allena Pharmaceuticals. J.M. received speaker honoraria and consultant fees from Ablynx, Alexion, and Sanofi-Genzyme. D.A.Eichenhauer has received speaker honoraria from Sanofi-Genzyme and Takeda. K.S. has received speaker honoraria from AbbVie, Merck, Pfizer, and Roche, consultant fees from AbbVie, Amgen, Bristol-Myers Squibb, Merck, Novartis, and Roche, and travel and congress fee compensation from AbbVie, Bristol-Myers Squibb, Celgene, Janssen Cilag, Lilly, and Servier. M.H. reports travel and congress fee compensation and speaker honoraria from Jazz Pharmaceuticals. P.K. reports travel support, participation in data safety monitoring boards and advisory boards, and consulting fees and/or speaker honoraria from Ablynx/Sanofi, Shire Roche, Novo Nordisk, CSL-Behring, and Biotest. F.B. reports speaker honoraria and consulting fees from Sanofi-Genzyme. A.G. reports consulting fees from Sanofi-Genzyme and Alexion and participation in advisory boards for Alexion. T.M. reports speaker honoraria from Sanofi-Aventis Deutschland GmbH. A.S. reports advisory board fees from Sanofi-Genzyme. K.S. reports speaker honoraria from AstraZeneca, Novartis, Takeda/Shire, and Vifor. M. K. reports speaker honoraria from Sanofi-Genzyme. All other authors report no conflict of interest., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)